Toshinobu Horii

Population Pharmacokinetic and Pharmacodynamic Analysis of Linezolid and a Hematologic Side Effect, Thrombocytopenia, in Japanese Patients

ABSTRACT Linezolid is an antimicrobial agent to treat infections by Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). While effective, linezolid treatment frequently is associated with hematological side effects, especially thrombocytopenia. However, little is known about the mechanism of this side effect and the exposure-response relationship. The present population pharmacokinetic/pharmacodynamic (PPK/PD) study was undertaken to elucidate the factors that determine linezolid levels, the relationship between exposure to linezolid and a decrease in platelet counts, and appropriate dosage adjustments based on exposure levels. In total, 50 patients (135 plasma samples) were used for the PPK analysis. The PPK analysis revealed that renal function and severe liver cirrhosis (Child Pugh grade C) significantly affect the pharmacokinetics of linezolid according to the equation clearance (liter/h) = 2.85 × (creatinine clearance/60.9)0.618 × 0.472CIR (CIR indicates cirrhosis status; 0 for noncirrhosis, 1 for cirrhosis patients). Using 603 platelet counts from 45 patients, a PPK/PD analysis with a semimechanistic pharmacodynamic model described the relationship between linezolid exposure and platelet counts quantitatively, and the newly constructed model was validated using external data (776 platelet counts from 60 patients). Simulation indicated considerable risks in patients with insufficient renal function (creatinine clearance, ≤30 ml/min) or severe liver cirrhosis. For these patients, a reduced dosage (600 mg/day) would be recommended for sufficient efficacy (area under the concentration-time curve over 24 h in the steady state divided by the MIC, >100) and safety.

Anaerobic bacteremia: the yield of positive anaerobic blood cultures: patient characteristics and potential risk factors.

Abstract The anaerobic blood culture (AN) bottle is routinely used in Japan with little discussion as to its justification or validity. We retrospectively studied the AN bottle yield of obligate anaerobes and the characteristics of, and potential risk factors in, patients with anaerobic bacteremia during a 2-year period (1999–2000) at four university hospitals and one community hospital. Thirty-four of 18310 aerobic and anaerobic blood culture sets from 6215 patients taken at the university hospitals, and 35 of 2464 samples taken from 838 patients at the community hospital, yielded obligate anaerobes. Bacteroides species and Clostridium species accounted for 60% of the isolates. Fifty-seven patients from 69 blood culture sets containing anaerobes had clinically significant anaerobic bacteremia. Among these 57 patients, 24 (49%) were oncology patients, 40 (70%) had an obvious source of anaerobic infection, 15 (26%) had recent surgery and/or were in an immunosuppressed state. We concluded that the recovery rate of obligate anaerobes isolated from AN bottles was low, and the patients with anaerobic bacteremia had limited number of underlying diseases or potential risk factors for anaerobic infections. Therefore, anaerobic blood cultures may be selectively used according to the potential risk for anaerobic infections.

Use of a dual priming oligonucleotide system to detect multiple sexually transmitted pathogens in clinical specimens

Aims:  To evaluate a new dual priming oligonucleotide (DPO)‐based multiplex polymerase chain reaction (PCR) assay for detection of six sexually transmitted pathogens, including Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium, Mycoplasma hominis, Ureaplasma urealyticum and Trichomonas vaginalis.

Bacillus cereus from blood cultures: virulence genes, antimicrobial susceptibility and risk factors for blood stream infection

We characterized the profiles of virulence genes and antimicrobial susceptibility of Bacillus cereus isolates from blood cultures as well as the risk factors for blood stream infections (BSIs). The diversity of virulence gene patterns was found to be wide among 15 B. cereus isolates from BSIs and also among 11 isolates from contaminated blood cultures. The MicroScan broth microdilution method yielded results corresponding with those of the agar dilution (reference) method for levofloxacin, linezolid, and vancomycin, while the Etest results were consistent with the reference results for clindamycin, gentamicin, imipenem, levofloxacin, and linezolid. Compared with the reference values, however, some isolates showed marked differences of the minimum inhibitory concentrations (MICs) for ampicillin and clindamycin when determined using the MicroScan method, or the MICs for ampicillin, meropenem, and vancomycin when determined using the Etest method. Significantly more patients were treated with antimicrobials for more than 3 days during the 3-month period before isolation in the BSI group. Prior antimicrobial therapy may be a risk factor for BSIs due to B. cereus.

Blood stream infections caused by Acinetobacter ursingii in an obstetrics ward

The genus Acinetobacter is an important causative pathogen of nosocomial infections in the healthcare setting. The objectives of this study were to determine the species of causative pathogens and the sources of Acinetobacter blood stream infections that occurred in 2 immunocompetent pregnant women admitted to an obstetrics ward within a 2-month period. Phenotypic identification of the two isolates from blood stream infections was inconsistent among the ID test, the MicroScan WalkAway and the Vitek2 systems. In addition to the growth profile and detailed biochemical analysis, genotypic identification and phylogenetic tree analysis based on the almost complete 16S rRNA sequence and the partial rpoB gene sequence confirmed the identification of these isolates as A. ursingii. Environmental investigation of the obstetrics ward revealed A. ursingii and different strains of Acinetobacter junii in specimens obtained from the ward shower bath, although the source and route of transmission for the A. ursingii infections were not clarified. Our findings show that A. ursingii can inhabit the hospital environment.

Bacillus cereus Bloodstream Infection in a Preterm Neonate Complicated by Late Meningitis

Central nervous system infections caused by Bacillus cereus have rarely been reported in infants. In this paper, the case of a 2-month-old low-birth-weight female who developed meningitis 45 days after resolution of a bloodstream infection (BSI) is described. The pulsed-field gel electrophoresis results revealed that the patterns of both B. cereus isolates responsible for the acute meningitis and for the prior bacteraemic episode were closely related. Although the source of the infection from within the patient was not clear, it is suggested that the B. cereus BSI developed in the neonate was complicated by acute meningitis.

Reactive Legionella pneumophila arthritis diagnosed by polymerase chain reaction

Legionellosis is a systemic infectious disease which involves primarily the lower respiratory tract with various extrapulmonary manifestations such as sinusitis, cellulitis, pancreatitis, peritonitis, and pyelonephritis [1]. However, there is limited information about joint complication with Legionella pneumophila. Recently, Andereya et al. [2] described the reactive arthritis as an atypical extrapulmonary manifestation of L. pneumophila infection in this journal. Several microbiologically proven septic arthritis with L. pneumophila have also been reported [3, 4]. We describe a case of Legionella arthritis (LA) diagnosed by the polymerase chain reaction (PCR) method. An 80-year-old woman with chronic renal failure presented with cough, fever, and fatigue. She had no joint symptoms at the initial presentation. Chest radiograph showed a consolidation on the left lower lung Weld. Blood and sputum cultures were sterile, but the urinary antigen for L. pneumophila serogroup 1 was detected (Binax NOW Legionella). She was diagnosed as having L. pneumophila pneumonia. After administering intravenous ciproXoxacin for 2 weeks, symptoms and radiographic Wnding had almost improved. However, 2 days after switching antimicrobials to oral levoXoxacin, the left ankle began to swell. The swelling subsequently spread to the right ankle and high fever relapsed. White blood cell (WBC) count and serum C-reactive protein level increased. Chest radiograph showed no evidence of the recurrence of pneumonia. Magnetic resonance imaging of the joints revealed increasing of articular Xuid. Aspiration of the joints yielded a white purulent Xuid with a WBC count of 50,000 per mm3, but Gram stains revealed no organisms. Aerobic and anaerobic cultures of the specimens including buVered charcoal yeast extract plate culture were negative. Polarization microscopy revealed no crystalline structures in the specimens. Serum rheumatoid factor and antinuclear antibodies were negative. Finally, articular Xuid was found to be positive for L. pneumophila by PCR amplifying 245 base-pair fragment of 16S ribosomal DNA gene [5]. Fever and joint symptoms relieved within a few days after re-starting intravenous ciproXoxacin and she had recovered from arthritis without any restriction of movement in her joints. Extrapulmonary legionellosis in joints is an extremely rare condition. Previously reported cases and our case shared several characteristics (Table 1). First, small joints such as wrists and ankles were multiply aVected. Second, all cases showed slow progression with more than 2 weeks of the duration of symptoms. These presentations were rather similar with noninfectious arthritis such as rheumatoid arthritis or pseudogout, because septic arthritis was usually monoarticular, aVecting larger joint such as knee or hip, and aggressively destroys the joint within a few days. Third, the onset of the articular symptoms was not always coincident with pneumonia. Cases 1 and 4 developed arthritis after treatment of pneumonia and case 3 had no obvious evidence of pneumonia. In addition to these atypical presentations, the poor sensitivity T. Naito · T. Suda (&) · K. Saga · K. Chida Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, 431-3192, Japan e-mail: suda@hama-med.ac.jp

BK virus nephropathy: Clinical experience in a university hospital in Japan

Objectives:  To review the medical records of patients with BK virus nephropathy (BKVN) following kidney transplantation in our institution.

Detection of carbapenem resistance in clinical mucoid Pseudomonas aeruginosa isolates.

Of 19 isolates of mucoid Pseudomonas aeruginosa, 2 isolates showed imipenem resistance conferred by reduced OprD production. Imipenem resistance was detected by the MicroScan broth microdilution and Etest methods, but minimum inhibitory concentrations could not be determined by the Vitek system for an isolate. In cases where susceptibility cannot be determined by the broth microdilution methods, Etest results would be valuable for effective treatment.